title: Identification of succinate dehydrogenase-deficient bladder paragangliomas.
abstract: A significant number of patients with paragangliomas harbor germline mutations in one of the succinate dehydrogenase (SDH) genes (SDHA, B, C, or D). Tumors with mutations in SDH genes can be identified using immunohistochemistry. Loss of SDHB staining is seen in tumors with a mutation in any one of the SDH genes, whereas loss of both SDHB and SDHA expression is seen only in the context of an SDHA mutation. Identifying an SDH-deficient tumor can be prognostically significant, as tumors with SDHB mutations are more likely to pursue a malignant course. Although the rate of SDH deficiency in paragangliomas in general is known to be approximately 30%, there are only rare reports of SDH-deficient bladder paragangliomas. Therefore, the aim of this study was to determine the rate of SDH deficiency in bladder paragangliomas. Eleven cases of bladder paragangliomas were identified. Hematoxylin and eosin-stained slides of all tumors were reviewed, and immunohistochemical analysis for SDHB and SDHA was performed. For cases with loss of SDHA expression by immunohistochemistry, mutation analysis of the SDHA gene was performed. Loss of SDHB staining was seen in 3 (27%) cases (2 with loss of SDHB only, 1 with loss of SDHB and SDHA). Patients with SDH-deficient tumors were younger than those with tumors with intact SDH expression (mean age at presentation 39 y and 58 y, respectively). Of the 2 patients with SDHB-deficient and SDHA-intact tumors, one was found to have a germline SDHB mutation, and the other had a family history of a malignant paraganglioma. Both patients developed metastatic disease. The one patient with a tumor that was deficient for both SDHB and SDHA had no family history of paragangliomas and no evidence of metastatic disease. Sequencing of this tumor revealed a deleterious heterozygous single-base pair substitution in exon 10 of SDHA (c.1340 A>G; p.His447Arg) in both the tumor and normal tissue, indicative of a germline SDHA mutation, and a deleterious single-base pair substitution in exon 5 of SDHA (c.484 A>T; p.Arg162*) in 1 allele of the tumor only. No patients with intact SDH expression had a family history of paragangliomas; 1 had a synchronous paraganglioma, but none developed metastatic disease. A significant subset of bladder paragangliomas is SDH deficient. It is essential to identify SDH-deficient tumors, as the presence of an SDH mutation has prognostic implications and is important in guiding genetic counseling.
authors.affiliation: *Department of Pathology, Brigham and Women's Hospital, Harvard Medical School †Department of Pathology, Massachusetts General Hospital, Harvard Medical School ‡Dana-Farber Cancer Institute, Center for Sarcoma and Bone Oncology, Harvard Medical School, Boston, MA §Department of Pathology, The Ottawa Hospital, Ottawa, ON, Canada.
authors.forename: Emily F
authors.initials: EF
authors.lastname: Mason
authors.forename: Peter M
authors.initials: PM
authors.lastname: Sadow
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Wagner
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Remillard
authors.forename: Trevor A
authors.initials: TA
authors.lastname: Flood
authors.forename: Eric C
authors.initials: EC
authors.lastname: Belanger
authors.forename: Jason L
authors.initials: JL
authors.lastname: Hornick
authors.forename: Justine A
authors.initials: JA
authors.lastname: Barletta
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000032:analysis / Q000096:biosynthesis; D008297:Male; D008875:Middle Aged; D010236:Paraganglioma, Extra-Adrenal / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D012189:Retrospective Studies; D013385:Succinate Dehydrogenase / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics*; D001749:Urinary Bladder Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D055815:Young Adult
chemical_list: D007527:Isoenzymes; D013385:Succinate Dehydrogenase